Male Infertility Evaluation

Facts:
15% couples unable to conceive at first year of
unprotected intercourse
Male factor: 20% (sole infertility factor)
30-40% (contributory)

Therefore: Male factor is

approximately 50%
responsible in infertility
n Male attitude or “ego” “The
problem is usually due to
the female partner”

n The idea that most

Urologists are not trained or
interested in male infertility
patients

– AUA 2008
When to do evaluation
for male infertility:
n Pregnancy fails to occur with 1 year of
regular unprotected intercourse
u Pregnancy rate: 2-3% per month
u 25-30% will eventually conceive without
treatment
n Do before 1 year when:
u Known male infertility risk factors
u Female infertility risk factors
u Couple questions male fertility potential
Infertility classifications
n Pre-testicular
u Hormone Deficiency
n Testicular
u Impaired sperm production
« Genetic
« Varicocele
n Post-testicular
u Obstruction
u Anti-sperm antibodies
u Infection
Terms:

n Primary Infertility – has never

initiated a pregnancy
n Secondary Infertility – had initiated
pregnancy before but currently has
difficulty or unable to initiate
pregnancy
n Infertile male
n Subfertile male
Initial Evaluation for
male infertility:
History Physical Exam Semen analysis

Differential diagnosis

Additional Lab tests

Final Diagnosis
History:
n 6 issues that needs to be
addressed

u Sexual History
u Pregnancy History

u Current Medications

u Childhood illnesses

u Medical /Surgical
problems
u Gonadotoxins
n Sexual History:
u Does the partner have regular cycles?
u Does she know when she ovulates?

u Erectile dysfunction problems?

u Sexual technique, use of lubricants, frequency and

timing of coitus

n Pregnancy History:
u Previous pregnancies?
u History of repeated miscarriages?
n Medications
u Steroid/steroid products
u All forms of administered testosterone

u Medications i.e antidepressants, alpha adrenergic

blockers, nitrofurantoin, cimetidine

n Childhood diseases:
u Torsion/Trauma
u Cryptorchidism/ Tumor

u Mumps orchitis

u CBAVD
n Medical/Surgical Illnesses:
u Surgical Procedures that may impair
ejaculation/testicular function
« Retroperitoneal surgery
« Pelvicinjury
« Herniorraphy

« TURP

u Medical illnesses
« Diabetes Mellitus
n Gonadotoxins:
u Tobacco
u Chemotherapy

u Radiotherapy

u Alcohol

u Steroids

u Pesticides

u Heat
Physical examination
Physical Examination
n Constitutional
u Vital Signs
u General appearance

« Hairdistribution
« Eunichoid

n Psychiatric
u Orientation
u Mood/Affect

n Neck
u Appearance
u Thyroid
Physical Examination

n Genito-Urinary
u Penis
« Meatus

u Scrotum
« Testis
• Position
• Size
• Consistency
« Epididymis

« Vas deferens
« Varicocele
Varicocele

Incidence
%
General Population 13.4%
Infertile Male population 37.0%

Ultrasound Criteria: > 3mm

reversal of flow
Varicocele
n Diagnose by physical exam
u Warm room
u Standing

u Increase abdominal pressure

« Push belly out
« Valsalva
n Varicocele Grading
u Subclinical – do not search or repair
u Grade I –small

u Grade 2- medium

u Grade 3- large
Semen analysis
Technical aspects of the semen analysis
n Non-specialized laboratories
u Inadequate equipment

u Untrained personnel

u Time of examination

n Improper collection
u Timing of collection
( duration of abstinence)
u Receptacles used for
collection
u Completeness of collection
Semen analysis
n Minimum of 2 collections
n Give directions on proper collection
u Abstain 3-7 days
u Keep at body temperature

u Bring to laboratory within 60-90 mins

n Collection Technique
u Masturbation in a clinical setting
u Masturbation with assistance (PDE 5 inhibitors,
seminal pouches
u Vacuum erection devices

u Vibratory stimulation and electroejaculation

n Semen Thresholds
u What are “normal” thresholds?
« Averagesperm density of 70-100M/ml
« Lower Reference threshold for Normal fertile male
15M/ml

u Thresholds are not the same for IUI,IVF and ICSI

Lower reference limits (WHO 5th ed. 2010)
Parameter Lower reference limit (5th
percentile and 95%
confidence intervals)
Semen Volume 1.5 (1.4-1.7)

Total Sperm number (10 6 per 39 (33-46)

ejaculate)
Sperm concentration ( 10 6 per 15 (12-16)
ml)
Total motility (PR+NP)% 40 (38-42)

Progressive motility (PR%) 32 (31-34)

Vitality (live spermatozoa %) 58 (55-63)

Sperm Morphology (normal 4 (3.0-4.0)

forms %)
Other consensus threshold Lower reference limit
values
pH > 7.2

Peroxidase positive leukocytes <1.0

(106 per ml)
MAR test (motile spermatozoa <50
with bound particles %)
Immunobead test (motile <50
spermatozoa with bound beads
%)
Seminal Zinc ( umol/ejculate) > 2.4.

Seminal fructose (umol > 13

/ejaculate)
Seminal neutral glucosidase > 20
(mU/ejaculate)
n Volume
u Incomplete collection is the most common
cause
u Low volume: retrograde ejaculation, short
duration of sexual abstinence
u < 6ml : prolonged sexual abstinence

n Concentration
u Most widely used semen parameter
u Low counts (oligospermia) can be due to
incomplete collection or short sexual
abstinence
u Absence of sperm (azoopermia) -ejaculatory
dysfunction, obstruction, abnormal
spermatogenesis
n Motility
u Less than 5% motility- ultrastructural defects
(flagella)
u Zero motility: r/o necrospermia

u Best independent predictor of IUI success

u with sperm concentration : provides accurate

prediction of fertility with high sensitivity and
specificity
n Vitality
u Not part of regular semen analysis and needs to
be requested separately when there is no or
very low motility
u Aid selection of sperm for IVF

n Morphology
u Low normal (teratozoospermia)- epididymal
dysfunction, varicocele
u Debates on its importance in determining fertility

u In ICSI percent normal is not important as long

as the tech can find the same number of normal
sperm as there are eggs to inject
Basic Semen Parameter conclusions:
n There is no single test that can absolutely confirm
an individual’s fertility or infertility
n It should be emphasized that semen parameters
display very wide intra and inter individual
variations
n More than one specimen is required to establish
that a man consistently produces abnormal
semen
n Low parameters or scores do not exclude pregnancy
by IUI, IVF or intercourse
Differential Diagnosis based on Semen Analysis
1. Low Ejaculate Volume
a) Drugs
b) Retroperitoneal or bladder neck surgery
c) Ejaculatory duct obstruction
d) Diabetes mellitus
e) Spinal cord injury
f) Psychologic disturbances
g) Idiopathic
h) Incomplete collection

2. Azoospermia
a) Hypogonadotropic hypogonadism
i. Kallman syndrome
ii. Pituitary tumor
b) Spermatogenic abnormalities
c) Chromosomal abnormalities
d) Y-chromosome microdeletions
e) Gonadotoxins
f) Varicocele
g) Viral orchitis
h) Torsion
i) Idiopathic
j) Ductal obstruction
Additional Tests

n Most patients do not need additional tests

n Use tests to narrow down the differential diagnosis
Analysis finding Possible follow-up test

Ejaculate Low (<1.5 mL) Post ejaculate volume (retrograde ejac.)

volume TRUS (absence of vas deferens)
Hormonal evaluation

Semen quality Does not coagulate TRUS (ejac. Duct obst)

Does not liquify Hormonal analysis

Sperm density Oligospermia (<15M/ml) TRUS (partial ejac duct obst)
Severe oligospermia Anti sperm antibody
(<5M/ml) Hormonal analysis
PE for varicocele
Sperm centrifuged to verify
Post ejaculation urine

Azoospermia hormonal
Testicular biopsy (testicular failure)
TRUS(ejac. Duct obst)
Motility Decreased Anti sperm antibodies
PE for varicocele
Additional Tests
n Hormone Levels
n Genetic Testing
n Post ejaculate urine
n Ultrasonography
n Antisperm Antibody Assays
n WBC testing
n Sperm Function Testing
u PCT
u Sperm penetration assay
u Zona binding/acrosome reaction assays
u DNA integrity assays
Hormone Testing

n Indications:
u Sperm Density <10M/ml
u Sexual Dysfunction

n Initial Screening
u FSH
u Testosterone -Early AM

« Bioavailable assay or Free testosterone

n Follow up if initial tests are abnormal
u FSH, T, LH, prolactin
n Normal FSH with normal bilateral testicular
volume – high likelihood of obstruction
n 29% with normal FSH have defective
spermatogenesis

n Hypergonadotropic hypogonadism (elevated

FSH/LH)
u Generally not caused by disruption of endocrine
system
u Congenital ( Klinefelter’s synd., anorchia,
cryptochidism with dysgenesis, Y chromosome
microdeletions
u Acquired (post orchitis, testicular torsion,
systemic illness
n Hypogonadotropic hypogonadism (deficient
LH/FSH)
u Rare, and may due to dysfunction of pituitary or
hypothalamic dysfunction
u Congenital ( Idiopathic, Kallman’s synd)

u Acquired (tumor, hyperprolactinemia)

u Exogenous (anabolic steroids,obesity, irradiation)

u If unexplained , MRI or CT of the pituitary gland

should be requested
Genetic Testing- what tests?

n Patients to undergo IVF/ICSI with <5M/ml sperm

u Karyotyping
u Y chromosome analysis (microdeletions)

n Patients with vasal agenesis/unexplained epid. Obst.

u CFTR testing r/o CF mutations
n Unexpected pregnancy losses
u FISH (fluorescent in situ hybridization) of sperm
Y- chromosome microdeletions
n Reported in 1976 by Teipolo and zufferdi as deletions at Yq
in azoospermic patients
u Termed AZF (Azoospermia Factor)

n Incidence
u 0.7% oligospermia (<5M/ml)

u 10% severe oligospermia

u 15% azoopermia

n Frequency:

Yq11 incidence % No sperm/TESE

Region AZFa 5% Variable
AZFb 35% 100%
AZFc 60% variable
Sperm Aneuploidy and FISH

n Used to assess numerical chromosome

abnormalities
n Indications:
u Identify cause of recurrent spontaneous abortions
u Predict reason for IVF/ICSI failure

n Recent FISH data:

u In 29 patients with severe OAT, 93% with abnormal
FISH result
Alukal, et al, AUA 2007, Abstract #96944
n Chromosomal abnormalities common with
OAT and azoospermia
u MC: Klinefelter’s syndrome (47XXY)
affecting 10% of azoospermic men

n Genetic testing is important in cases of

habitual abortions and if ICSI will performed
since the defect will be passed on to sons
who will also have fertility problems
Post Ejaculate Urine Analysis

n Purpose
u Identify retrograde ejaculation
n Indications
u Low volume semen or absent ejaculate
u Not azoospermia

n Technique
u Void
u Collect semen sample
u Void into second container
Ultrasonography
n Scrotal ultrasound
u If PE is difficult to perform
u Testicular tumors -5% of infertile men

u Color Doppler can detect varicocele in 30% of

infertile males

n TRUS
u Low volume ejaculate
u Replaced fructose testing for seminal vesicles

u Detect obstruction of ejaculatory duct (caused by

midline prostatic cyst or stenosis of ejac. Duct)
Antisperm antibodies testing
n Indications:
u Microscopic Sperm clumping
u Unexplained poor PCT

u Isolated motility defect

u Unexplained infertility

u 10% infertile men will have positive ASA

n Immunobead assay
u Most accurate
u detect IgA and IgG antibodies binding to specific
portions of the sperm
n Anti sperm antibodies
u From disruption of the blood testis barrier
u High in couples with unexplained infertility

u Found in 60% of vasectomy patients –

however does not affect decision to proceed
with vasectomy reversal
u Low concentrations have little effect on fertility

u ASA affects: Motility, cervical mucus

penetration, capacitation, acrosome reaction,
binding and penetration of zona pellucida
WBC testing

n Can be done if high numbers of round cells are

present
n Distinguish immature sperm cells vs. leukocytes
n Endtz test (orthotoluidine dye test), monoclonal
antibody testing
n High WBC in sperm counts have high ROS
(reactive oxygen species) and correlates with poor
fertility potential
Viabilty testing
n Should be requested when motility is less than
5-10%
n Eosin-Nigrosin Test, Hyper-osmotic swelling
test (HOST)
n Differentiate necrospermia from immobile
sperm secondary to structural defects
(Kartagener’s synd, primary cilia dyskeniesia)
n Aid in the selection of viable sperm for IVF
Other tests

n ROS (reactive oxygen species)

u Directly damages sperm via lipid peroxidation
u By products of normal sperm, immature
spermatozoa and WBC
n DNA integrity
u Increased DNA abnormalities in infertile males
u > 27% will have IVF/ICSI failure
Sperm Function Tests

n HOS (hypo osmotic tests) , Acrosome testing,

Sperm penetration assay(SPA), DNA
fragmentation, Strict Morphology Index
n Important in determining if fertilization will take
place and if embryo will develop normally
n Morphology-the most readily available
u Patients with < 4% normal forms will have a fertility
rate of 7.6% (NV >50%)
« Represent a non-specific surrogate or a possible
global dysfunctional sperm fertility capacity
Biochemical testing
n Zinc
u From the prostate
u Necessary for chromatin stability and
decondensation

n Fructose
u From seminal vesicles
u Low in hypo functioning seminal vesicles
n Glucosidase
u Can differentiate obstructive and non-
obstructive azoospermia ( ductal
obstruction vs testicular failure)
u Marker for epididymal function and sperm
maturation
u Can predict IUI response as higher levels
may indicate better zona binding capacity
Testicular biopsy
n Diagnostic testicular biopsy done only in
azoospermic patients
n Differentiates obstructive from non-obstructive
azoospermia
n Bilateral testicular biopsy done but in cases of
marked discrepancy in size, biopsy can be
done on the larger testis only
n Patients with clinical findings of obstruction or
testicular failure need not undergo the biopsy
n Patients with non-obstructive azoospermia
considering IVF may consider possibility of
cryopreservation
n Results:
u Normal
u Hypospermatogenesis –reduction in the number of
all germinal elements
u Maturation arrest – may occur at level of primary,
secondary spermatocyte or spermatid stage
u Germ cell aplasia – Sertoli cell only syndrome

u End stage testis- atrophic testis with tubular

sclerosis. Absent germ cells. Sertoli cells may or
may not be present
n If repair will be done on the same setting a wet
preparation or a cytologic smear is done at the
time of biopsy
Vasography
n Should only be done at the
time of reconstruction
n Indicated in azoospermic men
with mature spermatozoa on
testicular biopsy
n Vasal fluid should be
examined for the presence of
sperm—if positive , a prolene
suture is passed towards the
ejaculatory duct to assess
distance of obstruction
Male infertility associated factors
and percentage of distribution
Idiopathic male infertility 31%
Maldescended testis 7.8%
Urogenital infection 8.0%
Disturbances of semen deposition and sexual 5.9%

General and systemic disease 3.1%

Varicocele 15.6%
Hypogonadism 8.9%
Immunologic factors 4.5%
Obstructions 1.7%
Other abnormalities 5.5%

EAU 2010
Prognostic factors
n Duration of infertility
u Cumulative pregnancy rate (2 yrs) of oligospermic
patients is 27%
n Primary or secondary infertility
n Semen analysis result
n Age and fertility of female partner
u Fertility potential reduced to 50% at 35 yrs old,
25% by 38 yrs old and < 5% at over 40 years
Treatment options:
n Improve fertility potential
u Correct underlying abnormalities
u Use of emperical therapies

n Improve conception without altering the male’s

fertility status
u Use of assisted reproductive techniques

n Bypass the male partner by utilizing donor

sperm or adoption
Varicocele
n Present in 15% of normal male population
n Can be present in up to 40% with male infertility
n 70% in secondary infertility
n Associated with impaired semen quality and
decreased Leydig cell function
n In diagnosis, the gold standard remains to be
physical examination as subclinical varicoceles
need not be repaired
Indications for Varicocele Repair
1. Adolescent-large lesion and testis
atrophy
2. Adolescent/adult-variocele and pain
3. Male factor infertility with adequate
maternal potential (>1 year)
4. Male factor infertility with azoospermia?
5. Not likely to work with genetic infertility
n Surgical
u Inguinal
« ModifiedIvanissivich
« Microsurgical technique

u Subinguinal
u Retroperitoneal (Palomo)

u Laparoscopic

n Percutaneous embolization
n Outcomes:

u Meta-analyses: 50-60% improvement in semen

variables; 30-40% pregnancy after repair
u Can result in sperm in ejaculate of azoospermic
men with severe hypospermatogenesis or late
maturation arrest
u 41% improvement in motility and morphology

u 21% improvement in sperm forward progression

u Improve serum FSH and Testosterone levels

n Prediction of successful repairs

u Lack of testicular atrophy (56% vs 33%)

u Sperm density of >50M/ejaculate (60% vs 35%)

u Sperm motility of 60% or more (60% vs 30%)

u Serum FSH < 300 ng/ml (46% vs 25%)

« Marks, Mcmahon, Lipshultz, 1986

n Semen analysis should be performed 4 months
after varicocele repair and monitored regularly for
1 year

n Persistence or recurrence of varicocele –

consider internal spermatic venography to
localize persistently refluxing veins

n Meta analysis shows that varicocelectomy is a

more cost effective than IVF as first line Tx
u 29.7% live birth probability vs 25.4%
n Surgical management:

u Vasectomy reversal (vasovasostomy/vasoepid)

u Inguinal Vasovasostomy for vas obstruction

u Vasospididymostomy for epididymal

obstruction
u TURED – for ejaculatory duct obstruction

n Sperm retrieval for obstructive azoospermia

u Vasal or epididymal aspiration
u MESA- higher yield

u PESA / TESA– quick and inexpensive but may

have insufficient sperm
n Treatment for ejaculatory problems:

u Retrograde ejaculation-
« alpha agonist (pseudoephedrine, ephedrine)
« Antihistamines (brompheniramine,)

« Imipramine (TCA)

« If medications fail: retrieve alkalanized post

ejaculate urine
u Anejaculation
« Alpha agonist or penile vibratory stimulation or
electroejaculation
n Non-surgical management:

u Hypogonadotropic hypogonadism: hCG + FSH

(given as hMG)
u Isolated FSH deficiency (rare) – hMG

u Endogenous androgen excess 2ndary to CAH –

glucocorticoid therapy
u Prolactin excess – bromcriptine and Cabergoline

u Lifestyle changes- cessation of smoking, avoid

heat exposure, identification of occupational
exposure
n Clomiphene citrate – commonly used for
idiopathic oligospermia
u Antiestrogen increase gonadotropins by
blocking feedback inhibition—increasing FSH,
LH and testosterone

n Testosterone (high dose rebound and low dose

continuous therapy)
u Contraceptive effect and not recommended for
treatment
n Anti-sperm antibodies (immunologic infertility)

n 2 approaches
u Suppress antibody formation
« Use of corticosteroids – varying results
« Intermediate cyclic corticosteroid regimen

u Select spermatozoa not bound by antibodies

for ART
n “Emperical treatments”

u L carnitine
u Vitamin C

u Vitamin E

u Zinc

u Arginine

n Guidelines for emperic treatments

u Administer for a minimum of 3-6 month period
so that at least one full spermatogenic cycle is
included
n There has been major advancements in treating
female infertility but male infertility is a much
neglected field

n The need to identify the causes of male infertility

should be emphasized to optimize fertility work-ups
and treatment

n Even with the advent of ART, male fertility work up

still play a major role
Thank you